Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential
Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the poss...
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Frontiers Media S.A.
2018-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00907/full |
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| author | Michela De Bellis Francesca Sanarica Alessia Carocci Giovanni Lentini Sabata Pierno Jean-François Rolland Diana Conte Camerino Annamaria De Luca |
| author_facet | Michela De Bellis Francesca Sanarica Alessia Carocci Giovanni Lentini Sabata Pierno Jean-François Rolland Diana Conte Camerino Annamaria De Luca |
| author_sort | Michela De Bellis |
| collection | DOAJ |
| description | Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies. |
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| id | doaj.art-e952504b995b4bb5af748b7a8f7bbd2c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T00:40:14Z |
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| spelling | doaj.art-e952504b995b4bb5af748b7a8f7bbd2c2022-12-21T23:24:25ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-01-01810.3389/fphar.2017.00907298758Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic PotentialMichela De Bellis0Francesca Sanarica1Alessia Carocci2Giovanni Lentini3Sabata Pierno4Jean-François Rolland5Diana Conte Camerino6Annamaria De Luca7Unit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyUnit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyUnit of Medicinal Chemistry, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyUnit of Medicinal Chemistry, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyUnit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyAXXAM S.p.A., Milan, ItalyUnit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyUnit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, ItalyMexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.http://journal.frontiersin.org/article/10.3389/fphar.2017.00907/fullvoltage-clamp recordingssodium channelskeletal muscleanti-myotonic agentmuscular dystrophymexiletine |
| spellingShingle | Michela De Bellis Francesca Sanarica Alessia Carocci Giovanni Lentini Sabata Pierno Jean-François Rolland Diana Conte Camerino Annamaria De Luca Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential Frontiers in Pharmacology voltage-clamp recordings sodium channel skeletal muscle anti-myotonic agent muscular dystrophy mexiletine |
| title | Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential |
| title_full | Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential |
| title_fullStr | Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential |
| title_full_unstemmed | Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential |
| title_short | Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential |
| title_sort | dual action of mexiletine and its pyrroline derivatives as skeletal muscle sodium channel blockers and anti oxidant compounds toward novel therapeutic potential |
| topic | voltage-clamp recordings sodium channel skeletal muscle anti-myotonic agent muscular dystrophy mexiletine |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00907/full |
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